MSC-Hydrogel Composite Systems for Knee Cartilage Repair and Osteoarthritis: A Systematic Review

Background: MSC-hydrogel composite systems were developed to overcome the poor cell retention and limited durability of conventional marrow stimulation and suspension-based MSC delivery. A rigorous synthesis of the clinical evidence is lacking. Objectives: To evaluate the safety and efficacy of MSC-hydrogel composite therapy for focal knee cartilage defects and knee osteoarthritis, and to assess the certainty of evidence using the GRADE framework. Methods: PROSPERO-registered systematic review (CRD420261393525), conducted and reported per PRISMA 2020 and SWiM. Five databases (Embase, PubMed/MEDLINE, Cochrane CENTRAL, Scopus, Web of Science) were searched in May 2026 without date, language, or design restrictions. Adults receiving MSCs co-delivered in a hydrogel carrier for knee cartilage pathology were eligible. Risk of bias was assessed using RoB 2 (RCTs) and ROBINS-I (non-randomized studies). Narrative synthesis following Popay et al. was the primary method; GRADE certainty was assessed per outcome domain. Results: Ten studies (N = 521) were identified. Eight studies fulfilled the predefined eligibility criteria for MSC-hydrogel composite interventions and formed the primary evidence synthesis. Two additional studies were retained as contextual comparators because they evaluated either hydrogel-based therapy without MSC administration or MSC therapy without a structured hydrogel carrier. Surgical MSC-hydrogel implantation was associated with improvements in cartilage repair. Intra-articular injection without a hydrogel scaffold produced synovitis reduction but no detectable structural regeneration at six months. No serious treatment-related adverse events were recorded. Risk of bias was serious or critical in seven of nine assessable studies; GRADE certainty was low to very low across all outcome domains. Conclusions: MSC-hydrogel composite implantation may provide favorable safety signals and directionally positive effects on cartilage repair, pain, and function, with seven-year follow-up data suggesting a possible durability advantage over marrow stimulation. However, adverse-event reporting was inconsistent, and certainty of evidence remains low or very low because most studies were non-randomized, single-center, and concentrated around one commercial platform. These findings are relevant to international cartilage-regeneration research because they identify key methodological limitations and trial-design priorities for translating MSC-hydrogel systems across different clinical and regulatory settings.